目前，抑郁癥治療藥物大多都有藥效遲緩的缺陷,，從服藥到見效往往需要幾周的時(shí)間,。抑郁癥往往對患者帶來嚴(yán)重的精神折磨,，而且影響患者工作生活能力,，因此,，臨床治療迫切需要藥效迅速的藥物。最近,，科學(xué)家研究發(fā)現(xiàn),，常用麻醉劑克他命能在數(shù)小時(shí)內(nèi)改善抑郁癥病情。相關(guān)論文發(fā)表在2008年2月的愛思唯爾期刊《生物精神病學(xué)》（Biological Psychiatry）上,。
克他命是一種n甲基d天冬氨酸 (NMDA)受體阻斷劑,。Maeng和同事在研究中發(fā)現(xiàn)，克他命抗抑郁癥機(jī)理在于它對α-氨基-3-羥基-5-甲基-4-丙酸(AMPA)受體的激勵(lì)作用,。這表明,，激勵(lì)A(yù)MPA受體能夠快速改善抑郁癥病情。
文章通信作者Husseini Manji博士說：“通過瞄準(zhǔn)新的藥物標(biāo)靶,，例如NMDA或AMPA,，我們也許能夠?qū)崿F(xiàn)迂回前進(jìn)的效果?；乇軐?dǎo)致目前的抗抑郁藥物療效遲緩的若干藥物作用階段,，從而達(dá)到快速起效的目的。目前的抗抑郁藥物最終作用目標(biāo)是一致的,，但有些藥物起作用要經(jīng)過若干生物化學(xué)步驟,，這浪費(fèi)了很多時(shí)間。現(xiàn)在,，我們發(fā)現(xiàn)了關(guān)鍵標(biāo)靶,，直接瞄準(zhǔn)標(biāo)靶，所以見效快,。”
克他命雖具有抗抑郁效果,，但還有一些明顯的缺陷?！渡锞癫W(xué)》雜志的編輯,，同時(shí)還受聘于耶魯大學(xué)醫(yī)學(xué)院和美國退役軍人協(xié)會(huì)康涅狄格醫(yī)療服務(wù)系統(tǒng)的醫(yī)學(xué)博士John H. Krystal說：“克他命作為迄今為止發(fā)現(xiàn)的唯一有效的NMDA受體阻斷劑會(huì)引起感知激變，損傷認(rèn)知力,。”同時(shí),，它和苯環(huán)己哌啶屬同一類藥物，有致幻等副作用,。Krystal同時(shí)指出：“能夠直接促進(jìn)谷氨酸受體活動(dòng)的藥物谷氨酸受體調(diào)控劑（AMPAkines）可能會(huì)產(chǎn)生與克他命相似的抗抑郁效果,，而且不具有副作用。”對谷氨酸受體調(diào)控劑（AMPAkines）的抗抑郁效果研究將成為下一步研究的重點(diǎn),。（科學(xué)網(wǎng) 荔濤/編譯）
生物谷推薦原始出處：
（Biological Psychiatry）,，doi:10.1016/j.biopsych.2007.05.028 ，Sungho Maeng, Husseini K. Manji
Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors
Sungho Maenga, Carlos A. Zarate Jra, Jing Dua, Robert J. Schloessera, Joseph McCammona, Guang Chena and Husseini K. Manji, a,
aLaboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health & Human Services, Bethesda, Maryland.
Received 7 August 2006; revised 14 May 2007; accepted 23 May 2007. Available online 23 July 2007.
Background
Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action.
Methods
The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine’s behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput.
Results
Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.
Conclusions
NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
